Cannabidiol triggers fatty acids β-oxidation mediated by Stat2 to facilitate intestinal stem cells regeneration post radiation

www.nature.com/emm ARTICLE OPEN Cannabidiol triggers fatty acids β-oxidation mediated by Stat2 to facilitate intestinal stem cells regeneration post radiation Zebin Liao1,5, Congshu Huang2,5, Liangliang Zhang3,5, Changkun Hu3, Zekun Wu4, Zhijie Bai1, Gaofu Li1, Lei Zhou1, Ningning Wang1, ✉ ✉ ✉ Chaoji Huangfu1, Zhexin Ni1, Pan Shen 1 , Wei Zhou 1 and Yue Gao1 1234567890();,: © The Author(s) 2026 The development of compounds triggering intestinal stem cells (ISCs) proliferation represents a promising strategy to alleviate irradiation (IR)-induced gastrointestinal syndrome. Here, cannabidiol (CBD)-a nonpsychotomimetic phytocannabinoid derived from the Cannabis sativa plant-was found to dramatically improve body weight loss of mice and stimulate Lgr5+ ISCs proliferation upon a lethal dose of IR. Using absolute quantitative lipidomics, we found that the dysregulation of fatty acids in crypts induced by IR was rescued by CBD, which was indispensable for ISCs regeneration. Integrative analysis of transcriptome and lipidomics unveiled the critical role of PPARα in regulating fatty acid β-oxidation (FAO) by transcriptionally upregulating Slc27a2 and Acox1. Further experiments showed that CBD could trigger the enrichment of Stat2 on the promoter region of Pparα, ultimately facilitating the FAO program and subsequent ISCs proliferation following IR exposure. In addition,THOC3 was identified as a direct target of CBD, which stabilized the THOC3 protein and substantially alleviated the IR-induced blockade of Stat2 mRNA nuclear export. This study reveals a connection between CBD-driven ISCs proliferation and the FAO program during IR damage, providing a promising avenue for IR-induced gastrointestinal syndrome treatment. Experimental & Molecular Medicine; https://doi.org/10.1038/s12276-026-01711-5 Graphical Abstract The binding of CBD to THOC3 maintains its radiation stability, which then supports the nuclear export of Stat2 mRNA for the subsequent transactivation of Pparα. The upregulation of PPARα will ultimately stimulate the FAO program, thereby facilitating ISCs regeneration during IR exposure. INTRODUCTION The rapid self-renewal of the intestinal epithelium renders it particularly vulnerable to high-dose irradiation (IR) from nuclear leak or intensive radiotherapy for abdominal and pelvic neoplasms treatment1. As the small intestine regenerates about once every 3 days, insufficient compensation for the extensive loss of tissues will inevitably cause gastrointestinal syndrome (GIS) characterized by diarrhea, bloating, bleeding, nausea, fecal urgency and even 1 Academy of Military Medical Sciences, Beijing, China. 2Traditional Chinese Medicine School, Henan University of Chinese Medicine, Zhenzhou, China. 3Tianjin University of Traditional Chinese Medicine, Tianjin, China. 4College of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, China. 5These authors contributed equally: Zebin Liao, Congshu Huang, Liangliang Zhang. ✉email: ; ; Received: 12 February 2025 Revised: 9 December 2025 Accepted: 8 February 2026 Z. Liao et al. 2 death2. Nowadays, approximately 50–60% of patients with cancer receive radiotherapy, but GIS induced by IR has confined the dose escalation for better curative effects3. Nevertheless, there is currently no US Food and Drug Administration (FDA)-approved countermeasures for IR-induced GIS and the unmet medical needs are unmet. Intestinal stem cells (ISCs) expressing leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5) are the primary source for maintaining the crypt–villus structure4. Extensive research has demonstrated the critical role of ISCs in functional intestinal cell differentiation to maintain physiological homeostasis or the continual regeneration of intestinal epithelium5,6. As the number of Lgr5+ ISCs decreases rapidly and dramatically upon IR exposure, the development of drugs protecting these cells could be a potential therapeutic avenue for IR-induced GIS. The processes involved in the metabolic program of fatty acids (FAs) that are secreted upon the lipolysis of neutral lipids has been demonstrated to favor ISCs maintenance and function7. FAs can be metabolized by β-oxidation in peroxisomes or mitochondria to produce substrates for energy metabolism and acetyl-CoA for chromatin remodeling, maintaining the pluripotency and proliferation of ISCs8–10. For instance, short-term fasting or stimulation of the peroxisome proliferator-activated receptor (PPAR) family, hepatocyte nuclear factor 4 (HNF4) or PR-domain containing 16 (PRDM16) ultimately activate the FAs β-oxidation (FAO) program or genes, thereby increasing the number of ISCs and enhancing their self-renewal potentiality11–14. Furthermore, genetic ablation of the rate-limiting enzyme in FAO (Cpt1a) or inhibition of PPARα with cholic acid impeded FAO and markedly decreased ISCs numbers and function11,15. Correspondingly, supplementation with FAO substrates, such as short-chain FAs (propionic acid and butyric acid) derived from microbial groups, or FAO products (β-hydroxybutyric acid or acetic acid) sustained and improved ISCs function16,17. By contrast, disruption of the Arf1-mediated lipolysis pathway or the acetyl-CoA carboxylase 1 (ACC1)-mediated de novo fatty acid synthesis pathway resulted in a marked decline in ISCs7,18. However, current studies are only beginning to determine the crucial role of fatty acid metabolism in ISCs, and the detailed mechanisms regulating fatty acids mobilization, catabolism, biosynthesis and transport in response to external stimuli remain largely unclear. Furthermore, no therapeutic agents or strategies have been reported to promote ISCs-driven intestinal regeneration by targeting fatty acid metabolism or mobilization following IR exposure. Cannabidiol (CBD) is a nonpsychotomimetic phytocannabinoid derived from the Cannabis sativa plant, which possesses many therapeutic properties. With very low toxicity (the LD50 is 212 mg/ kg for rhesus monkeys19) CBD alone (Epidiolex) or in combination with tetrahydrocannabinol (THC) (Sativex/Nabiximols) have been licensed for the treatment of seizures associated with Lennox–Gastaut syndrome, Dravet syndrome and tuberous sclerosis20 and spasticity in moderate to severe multiple sclerosis21, respectively. CBD is also a promising compound for gastrointestinal tract diseases, of which refractory chemotherapyinduced nausea and vomiting22, intestinal bowel diseases23 and permeability in the human colon24 could be markedly eased with CBD treatment. In recent years, CBD has been demonstrated to modulate the proliferation, migration, metabolism or differentiation of stem cells. For instance, CBD treatment has been shown to confine the overactivation of radial neural stem cells, thereby maintaining normal neurogenesiss25; attenuate endoplasmic reticulum stress, thus protecting oligodendrocyte progenitor cells from inflammation-induced apoptosis26; enhance the viability and proliferation of skeletal (...truncated)